Understanding the pathophysiology of cardiac aging has never been more important. We recently identified the TGF family member GDF11 as an age-related hormone, with increased levels of GDF11 in the blood of young mice compared to old mice. The beneficial effect of increasing GDF11 in old animals is not limited to the heart, as our studies show that administration of GDF11 to old mice can restore skeletal muscle function as well as angiogenesis in the brain. These new data indicate that systemic GDF11 may provide constant signaling in mammals, and changes in the level of this protein may regulate organ function with advancing age. While it is attractive to imagine that administration of GDF11 could improve function in age- related diseases in humans with low levels of GDF11, it is critical first to consider that almost nothing is known about tonic GDF11 signaling in the context of adult mammalian myocardium. Our new findings show that GDF11, previously considered as a morphogen for embryonic development, provides previously unrecognized systemic and tonic signaling in adult mammals. Thus, it is critical to understand the effects of gain and loss of this tonic signaling in the myocardium. Here, using protein therapy to increase tonic GDF11 signaling and using inducible genetic loss of GDF11 in mice, we will pursue the following hypothesis-testing Aims, which we believe are essential for understanding the GDF11 pathway in aging myocardium: Aim 1: To test the hypothesis that tonic GDF11 signaling controls cardiomyocyte atrophic pathways. Here we will determine if GDF11 activates molecular atrophy pathways in cardiomyocytes in vitro and in vivo. We will determine if GDF11 signaling in the heart is through canonical signaling pathways using mice with cardiomyocyte-specific deletions of Alk4, SMAD2, and SMAD3. We will also determine if loss of tonic GDF11 signaling changes these pathways using inducible systemic loss of GDF11 as well as cardiomyocyte- specific loss of GDF11 in mice. Aim 2: To test the hypothesis that tonic GDF11 signaling regulates the cardiac hypertrophy response after transverse aortic constriction (TAC) in young and old mice. GDF11 can reverse age- related cardiac hypertrophy in the absence of pressure overload, but the effect on pressure overload hypertrophy is unclear. Here we will test the hypothesis that increasing tonic GDF11 (with recombinant protein) or decreasing tonic GDF11 (with inducible genetic loss of GDF11) after TAC can regulate cardiac hypertrophy. Furthermore, diastolic properties of the left ventricle will be evaluated by ex vivo and in vivo measurements. Aim 3: To test the hypothesis that tonic GDF11 signaling in mice reduces exercise-induced cardiac hypertrophy. Here we will test the hypothesis that systemic gain and loss of tonic GDF11 signaling will reduce exercise-induced cardiac hypertrophy in young and old mice. Mice with deletions in the canonical TGF signaling pathway will determine the specific molecular pathways that are activated.